This application is a response to RFA MH-92-15 pertaining to a 'Phase Two Cooperative Agreement for Genetic Studies Of Alzheimer's Disease' (AD). During Phase l, known as 'Diagnostic Centers for Psychiatric Linkage Studies', three research centers were funded to collect siblings pairs with AD. These investigators (from Harvard Medical School, Johns Hopkins Medical School and the University of Alabama), together with NIMH staff, have designed and implemented a common protocol whose goal is to collect a total of 400 sibling pairs with AD. This work is ongoing; to date, over 160 sibling pairs have been collected. During Phase 2, the three centers will continue to work together to identify the genes involved in AD, We plan to: l) Genotype sib-pairs and FAD pedigrees for polymorphic :markers spanning the human genome. 2) Assess affected members of the sib-pairs and FAD families for the presence of the three known mutations in the amyloid B protein precursor gene on chromosome 21 and other new ones which may arise in the course of the proposed studies. 3) Perform statistical analyses on the genotypic data as well as computer simulations to determine the best analytic strategy that should be employed to detect linkage, given genetic heterogeneity and the structures of the families being collected. 4) Type additional highly polymorphic markers in the relevant chromosomal region, once linkage has been found, to better define the region in which linkage has been found. 5) Maintain data in a computer database, with a common format across sites.